title: Immunoregulation by interleukin-12 in MB49.1 tumor-bearing mice: cellular and cytokine-mediated effector mechanisms.
abstract: Administration of recombinant murine interleukin (rmIL)-12 to MB49.1 tumor-bearing mice results in dose-dependent regression of the primary tumor and the generation of protective antitumor immunity in the majority of animals. rmIL-12 administration is associated with a marked increase in lymph node cellularity that is predominantly due to the expansion of B220+ B cells as well as CD8+ T cells. Stimulation of lymph node cells from rmIL-12-treated, but not control tumor-bearing mice, with MB49.1 tumor cells in vitro was shown to enhance the secretion of interferon (IFN)-gamma. The magnitude of this in vitro response was dependent on the dose of rmIL-12 administered in vivo and mirrored the change in circulating serum IFN-gamma. Furthermore, at the height of the in vitro response to tumor stimulation, the addition of a neutralizing antibody to murine IL-12 suppressed IFN-gamma production, indicating a role for endogenous IL-12 in this antigen-specific cytokine response. Although studies in SCID mice confirmed that an appropriate T cell response was required for rmIL-12-mediated antitumor activity, in immunocompetent animals early tumor regression was not accompanied by cellular infiltration of the tumor. In contrast, a profound increase in tumor-associated inducible nitric oxide synthase (iNOS) was observed in mice receiving rmIL-12 which preceded T cell infiltration of the tumor which could be detected during the second week of IL-12 treatment. Direct tumor killing through the cytotoxic actions of NO via the iNOS pathway may serve as a way of generating tumor antigen which enables the host to mount a subsequent T cell response against the tumor.
authors.affiliation: Department of Preclinical Research and Development, Genetics Institute, Andover, MA 01810, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Hunter
authors.forename: K E
authors.initials: KE
authors.lastname: Waldburger
authors.forename: D K
authors.initials: DK
authors.lastname: Thibodeaux
authors.forename: R G
authors.initials: RG
authors.lastname: Schaub
authors.forename: S J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: J P
authors.initials: JP
authors.lastname: Leonard
mesh_terms: D000818:Animals; D007111:Immunity, Cellular; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology
chemical_list: D011994:Recombinant Proteins; D018664:Interleukin-12